tbuckley/cabot-search huggingface dataset:
Injectable Sealants Based on Silk Fibroin for Fast Hemostasis and Wound Repairing
Authors: Peng Zhao, Peilang Yang, Wei Zhou, Haoyang Liu, Xin Jin, Xinyuan Zhu
Journal: Advanced Healthcare Materials (2023)

Uncontrollable blood loss poses fatality risks and most recently developed sealants still share common limitations on controversial components, degradability, mechanical strength or gelation time. Herein, series of injectable sealants based on silk fibroin (SF) is developed. Random coil/β-sheet conformation transition in SF is achieved by forming dendritic intermediates under induction of the structurally compatible and chemically complementary assembly peptide (Ac-KAEA-KAEA-KAEA-KAEA-NH2 , KA16 ). A ratio of 1:5 (KA-SF-15) shown an accelerating gelation process (≈12 s) and enhanced mechanical strength at physiological conditions. The interweaved nanofibers effectively impeded the bleeding within 30 s and no obvious adverse effects are observed. The supramolecular interactions and in vivo degradation benefit the inflammatory host cells infiltration and cytokines diffusion. Without any exogenous factors, the increased expression of VEGF and PDGF led to a positive feedback regulation on fibroblasts and vascular endothelial cell growth/proliferation and promoted the wound healing. These findings indicated the few assembly-peptide can accelerate fibroin gelation transition at a limited physiological condition, and the injectable amino acid-based sealants show obvious advantages on biocompatibility, degradability, rapid gelation and matched strength, with strong potential to act as next generation of biomedical materials.
Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor
Authors: Cuiqing Fan, Mark Wunderlich, Xiongwei Cai, Zijun Yan, Feng Zhang, Ashley Kuenzi Davis, Lingli Xu, Fukun Guo, Q Richard Lu, Mohammad Azam, Weidong Tian, Yi Zheng
Journal: Leukemia (2023)
Implantable Nerve Conduit Made of a Self‐Powered Microneedle Patch for Sciatic Nerve Repair
Authors: Xiangli Zhang, Yuanya Ma, Ziyan Chen, Hong Jiang, Zengjie Fan
Journal: Advanced Healthcare Materials (2023)

Abstract Peripheral nerve defects, particularly those of a larger size, pose a significant challenge in clinical practice due to their limited regenerative capacity. To tackle this challenge, an advanced self‐powered enzyme‐linked microneedle (MN) nerve conduit is designed and fabricated. This innovative conduit is composed of anodic and cathodic MN arrays, which contain glucose oxidase (GOx) and horseradish peroxidase (HRP) encapsulated in ZIF‐8 nanoparticles, respectively. Through an enzymatic cascade reaction, this MN nerve conduit generates microcurrents that stimulate the regeneration of muscles, blood vessels, and nerve fibers innervated by the sciatic nerve, eventually accelerating the repair of sciatic nerve injury. It is clear that this self‐powered MN nerve conduit will revolutionize traditional treatment methods for sciatic nerve injury and find widespread application in the field of nerve tissue repair.
Vitamin D supplementation in people with chronic kidney disease
Authors: Marc G. Vervloet, Simon Hsu, Ian H. de Boer
Journal: Kidney International (2023)

Vitamin D supplements have long been advocated for people with chronic kidney disease based on data from observational studies among the general population and people with chronic kidney disease. These data consistently suggested that higher circulating concentrations of 25-hydroxyvitamin D are associated with improved fracture, cardiovascular, cancer, and mortality outcomes. In the past few years, large clinical trials have been conducted to assess the effects of vitamin D supplements on a range of clinically relevant outcomes. Most of these studies were performed in the general population, but they also enrolled people with chronic kidney disease. Virtually all of these trials were negative and contradicted the observational data. In this review, the key observational data and clinical trials are summarized, and potential explanations for the discrepancies between these studies are discussed.
Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity
Authors: Lena R. Kaisinger, Katherine A. Kentistou, Stasa Stankovic, Eugene J. Gardner, Felix R. Day, Yajie Zhao, Alexander Mörseburg, Christopher J. Carnie, Guido Zagnoli-Vieira, Fabio Puddu, Stephen P. Jackson, Stephen O’Rahilly, I. Sadaf Farooqi, Laura Dearden, Lucas C. Pantaleão, Susan E. Ozanne, Ken K. Ong, John R.B. Perry
Journal: Cell Genomics (2023)

Obesity contributes substantially to the global burden of disease and has a significant heritable component. Recent large-scale exome sequencing studies identified several genes in which rare, protein-coding variants have large effects on adult body mass index (BMI). Here we extended such work by performing sex-stratified associations in the UK Biobank study (N∼420,000). We identified genes in which rare heterozygous loss-of-function increases adult BMI in women (DIDO1, PTPRG, and SLC12A5) and in men (SLTM), with effect sizes up to ∼8 kg/m2. This is complemented by analyses implicating rare variants in OBSCN and MADD for recalled childhood adiposity. The known functions of these genes, as well as findings of common variant genome-wide pathway enrichment analyses, suggest a role for neuron death, apoptosis, and DNA damage response mechanisms in the susceptibility to obesity across the life-course. These findings highlight the importance of considering sex-specific and life-course effects in the genetic regulation of obesity.
EZH2 targeting induces CD38 upregulation and response to anti-CD38 immunotherapies in multiple myeloma
Authors: Djamila Chemlal, Emmanuel Varlet, Amelie Machura, Sara Ovejero, Guilhem Requirand, Nicolas Robert, Guillaume Cartron, Elina Alaterre, Caroline Bret, Laure Vincent, Charles Herbaux, Giacomo Cavalli, Angélique Bruyer, Hugues De Boussac, Jerome Moreaux
Journal: Leukemia (2023)
Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling
Authors: Xue Liu, Jiao Li, Xuesong Yang, Xiaojie Li, Jing Kong, Dongyuan Qi, Fuyin Zhang, Bo Sun, Yuehua Liu, Tingjiao Liu
Journal: International Journal of Oral Science (2023)

Abstract Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.
Site-specific nanoswitch circumventing immune resistance via activating TLR and inhibiting PD-L1/PD-1 axis
Authors: Yanyun Hao, Hui Li, Xiaoyan Ge, Yang Liu, Jialin Yin, Xia Li, Yutong Liu, Hongfei Chen, Lingling Huang, Jing Zou, Shiying Zhang, Hao Wu, Zhiyue Zhang
Journal: Journal of Controlled Release (2023)
Single-cell dissection of cellular and molecular features underlying mesenchymal stem cell therapy in ischemic acute kidney injury
Authors: Wenjuan Wang, Min Zhang, Xuejing Ren, Yanqi Song, Yue Xu, Kaiting Zhuang, Tuo Xiao, Xinru Guo, Siyang Wang, Quan Hong, Zhe Feng, Xiangmei Chen, Guangyan Cai
Journal: Molecular Therapy (2023)

Mesenchymal stem cells (MSCs) exert beneficial therapeutic effects in acute kidney injury (AKI), while the detailed repair mechanism remains unclear. Herein, we probed the underlying mechanisms of MSC therapy in AKI by performing unbiased single-cell RNA sequencing in IRI model with/without MSC treatment. Our analyses uncovered the tubular epithelial cells (TECs) and immune cells transcriptomic diversity and highlighted a repair trajectory involving renal stem/progenitor cell differentiation. Our findings also suggested that profibrotic TECs expressing pro-fibrotic factors such as Zeb2 and Pdgfb promoted the recruitment of inflammatory monocytes and Th17 cells to injured kidney tissue, inducing TGF-β1 secretion and renal fibrosis. Finally, in addition to activating the repair properties of renal progenitor/stem cells, we uncovered a role for MSC-derived miR-26a-5p in mediating the therapeutic effects of MSCs by inhibiting Zeb2 expression and suppressing pro-fibrotic TECs and its subsequent recruitment of immune cell subpopulations. These findings may help to optimize future AKI treatment strategies.
A low-energy emulsification platform based on a Diet Coke–Mentos reaction-derived bubbly flow for formulating various emulsions as drug carriers
Authors: Yu-Jung Lin, Po-Kai Luo, Huei-Rou Su, Hung-Yun Lu, Wan-An Chang, Min-Chun Chiang, Hsin-Lung Chen, Kai Chen, Hao-Ji Wei, Kun-Ju Lin, Hsing-Wen Sung
Journal: Biomaterials (2023)
Methyltransferase-like proteins in cancer biology and potential therapeutic targeting
Authors: Ya-Nan Qi, Zhu Liu, Lian-Lian Hong, Pei Li, Zhi-Qiang Ling
Journal: Journal of Hematology & Oncology (2023)

Abstract RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N 6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.
Monensin induces secretory granule-mediated cell death in eosinophils
Authors: Marianthi Vraila, Elin Asp, Fabio Rabelo Melo, Mirjana Grujic, Ola Rollman, Gunnar Pejler, Maria Lampinen
Journal: Journal of Allergy and Clinical Immunology (2023)

Eosinophils contribute to the pathology of several types of disorders, in particular of allergic nature, and strategies to limit their actions are therefore warranted.We sought to evaluate the possibility of targeting the acidic, lysosome-like eosinophil granules as a potential means of inducing eosinophil cell death.To this end, we used monensin, an ionophoric drug that has previously been shown to permeabilize the secretory granules of mast cells, thereby inducing cell death.Our findings reveal that monensin induces cell death in human eosinophils, whereas neutrophils were less affected. Blockade of granule acidification reduced the effect of monensin on the eosinophils, demonstrating that granule acidity is an important factor in the mechanism of cell death. Furthermore, monensin caused an elevation of the granule pH, which was accompanied by a decrease of the cytosolic pH, hence indicating that monensin caused leakage of acidic contents from the granules into the cytosol. In agreement with a granule-targeting mechanism, transmission electron microscopy analysis revealed that monensin caused extensive morphological alterations of the eosinophil granules, as manifested by a marked loss of electron density. Eosinophil cell death in response to monensin was caspase-independent, but dependent on granzyme B, a pro-apoptotic serine protease known to be expressed by eosinophils.We conclude that monensin causes cell death of human eosinophils through a granule-mediated mechanism dependent on granzyme B.
Development of an mRNA-lipid nanoparticle vaccine against Lyme disease
Authors: Matthew Pine, Gunjan Arora, Thomas M Hart, Emily Bettini, Brian T Gaudette, Hiromi Muramatsu, István Tombácz, Taku Kambayashi, Ying K Tam, Dustin Brisson, David Allman, Michela Locci, Drew Weissman, Erol Fikrig, Norbert Pardi
Journal: Molecular Therapy (2023)

Lyme disease is the most common vector-borne infectious disease in the United States, in part because a vaccine against it is not currently available for humans. We propose utilizing the lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) platform to generate a Lyme disease vaccine like the successful clinical vaccines against SARS-CoV-2. Of the antigens expressed by Borrelia burgdorferi, the causative agent of Lyme disease, outer surface protein A (OspA) is the most promising candidate for vaccine development. We have designed and synthesized an OspA-encoding mRNA-LNP vaccine and compared its immunogenicity and protective efficacy to an alum-adjuvanted OspA protein subunit vaccine. OspA mRNA-LNP induced superior humoral and cell-mediated immune responses in mice after a single immunization. These potent immune responses resulted in protection against bacterial infection. Our study demonstrates that highly efficient mRNA vaccines can be developed against bacterial targets. Lyme disease is the most common vector-borne infectious disease in the United States, in part because a vaccine against it is not currently available for humans. We propose utilizing the lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) platform to generate a Lyme disease vaccine like the successful clinical vaccines against SARS-CoV-2. Of the antigens expressed by Borrelia burgdorferi, the causative agent of Lyme disease, outer surface protein A (OspA) is the most promising candidate for vaccine development. We have designed and synthesized an OspA-encoding mRNA-LNP vaccine and compared its immunogenicity and protective efficacy to an alum-adjuvanted OspA protein subunit vaccine. OspA mRNA-LNP induced superior humoral and cell-mediated immune responses in mice after a single immunization. These potent immune responses resulted in protection against bacterial infection. Our study demonstrates that highly efficient mRNA vaccines can be developed against bacterial targets.
Get out or die trying: Peptide- and protein-based endosomal escape of RNA therapeutics
Authors: Alexander Klipp, Michael Burger, Jean-Christophe Leroux
Journal: Advanced Drug Delivery Reviews (2023)

RNA therapeutics offer great potential to transform the biomedical landscape, encompassing the treatment of hereditary conditions and the development of better vaccines. However, the delivery of RNAs into the cell is hampered, among others, by poor endosomal escape. This major hurdle is often tackled using special lipids, polymers, or protein-based delivery vectors. In this review, we will focus on the most prominent peptide- and protein-based endosomal escape strategies with focus on RNA drugs. We discuss cell penetrating peptides, which are still incorporated into novel transfection systems today to promote endosomal escape. However, direct evidence for enhanced endosomal escape by the action of such peptides is missing and their transfection efficiency, even in permissive cell culture conditions, is rather low. Endosomal escape by the help of pore forming proteins or phospholipases, on the other hand, allowed to generate more efficient transfection systems. These are, however, often hampered by considerable toxicity and immunogenicity. We conclude that the perfect enhancer of endosomal escape has yet to be devised. To increase the chances of success, any new transfection system should be tested under relevant conditions and guided by assays that allow direct quantification of endosomal escape.
Neuroendocrine insights into neurosteroid therapy for postpartum depression
Authors: Doodipala Samba Reddy
Journal: Trends in Molecular Medicine (2023)

Postpartum depression (PPD) is associated with a decline in progesterone-derived anxiolytic-antidepressant neurosteroids after delivery. Neurosteroid replacement therapy (NRT) with GABA-A receptor-modulating allopregnanolone (brexanolone) shows promise as the first drug treatment for PPD. Here we describe the molecular insights of the neurosteroid approach for rapid relief of PPD symptoms compared with traditional antidepressants.
Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials
Authors: Zifan Zhao, Qin Zhao, Hu Chen, Fanfan Chen, Feifei Wang, Hua Tang, Haibin Xia, Yongsheng Zhou, Yuchun Sun
Journal: International Journal of Oral Science (2023)

Abstract Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.
Engineering nanoparticle toolkits for mRNA delivery
Authors: Bing Sun, Weixi Wu, Eshan A. Narasipura, Yutian Ma, Chengzhong Yu, Owen S. Fenton, Hao Song
Journal: Advanced Drug Delivery Reviews (2023)

The concept of using mRNA to produce its own medicine in situ in the body makes it an ideal drug candidate, holding great potential to revolutionize the way we approach medicine. The unique characteristics of mRNA, as well as its customizable biomedical functions, call for the rational design of delivery systems to protect and transport mRNA molecules. In this review, a nanoparticle toolkit is presented for the development of mRNA-based therapeutics from a drug delivery perspective. Nano-delivery systems derived from either natural systems or chemical synthesis, in the nature of organic or inorganic materials, are summarised. Delivery strategies in controlling the tissue targeting and mRNA release, as well as the role of nanoparticles in building and boosting the activity of mRNA drugs, have also been introduced. In the end, our insights into the clinical and translational development of mRNA nano-drugs are presented.
Black Phosphorus as a Targeting PPAR‐γ Agonist to Reverse Chemoresistance in Patient‐derived Organoids, Mice, and Pancreatic Tumor Cells
Authors: Shengwei Jiang, Weihan Liu, Dan Shi, Huan Cheng, Tingwei Deng, Guoyong Chen, Li Ma, Xianbin Zhang, Peng Gong
Journal: Advanced Healthcare Materials (2023)

Black phosphorus (BP) exhibits significant potential for clinical applications. However, further research is necessary to uncover the unknown biological functions of BP and broaden its applications across various fields. This study investigates the potential of BP as a targeting PPAR-γ agonist to overcome chemoresistance in the treatment of pancreatic adenocarcinoma (PAAD) using 2D and 3D cell lines, patient-derived organoids (PDOs), and mouse models. RNA-sequencing analysis shows that BP treatment enriches differentially expressed genes in the PPAR pathway, and molecular modeling predicts the potential docking site between BP and PPAR-γ. Transcriptional activity assays are further to verify the activation of PPAR-γ. BP-activated PPAR-γ inhibits cancer stem cell (CSC) properties and expression of biomarkers such as CD44 and c-Myc, which are involved in chemoresistance. Notably, CD44 overexpression in tumor cells renders them susceptible to BP while insensitive to gemcitabine. This indicates that BP preferentially targets stem-like cells, which exhibit heightened resistance to chemotherapeutic drugs. A combination treatment strategy involving BP and gemcitabine is developed, demonstrating enhanced treatment efficacy of PAAD in both in vitro and in vivo models. Thus, BP serves as a PPAR-γ agonist capable of reversing chemoresistance, establishing it as a potent anti-tumor approach for the treatment of PAAD.
A C/ebpα isoform specific differentiation program in immortalized myelocytes
Authors: Maria-Paz Garcia-Cuellar, Selin Akan, Robert K Slany
Journal: Leukemia (2023)

The transcription factor CCAAT-enhancer binding factor alpha (C/ebpα) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30) isoform. Mutations within the CEBPA gene selectively deleting p42 are frequent in human acute myeloid leukemia. Here we investigated the individual genomics and transcriptomics of p42 and p30. Both proteins bound to identical sites across the genome. For most targets, they induced a highly similar transcriptional response with the exception of a few isoform specific genes. Amongst those we identified early growth response 1 (Egr1) and tribbles1 (Trib1) as key targets selectively induced by p42 that are also underrepresented in CEBPA-mutated AML. Egr1 executed a program of myeloid differentiation and growth arrest. Oppositely, Trib1 established a negative feedback loop through activation of Erk1/2 kinase thus placing differentiation under control of signaling. Unexpectedly, differentiation elicited either by removal of an oncogenic input or by G-CSF did not peruse C/ebpα as mediator but rather directly affected the cell cycle core by upregulation of p21/p27 inhibitors. This points to functions downstream of C/ebpα as intersection point where transforming and differentiation stimuli converge and this finding offers a new perspective for therapeutic intervention.